Project Summary: Cerebral cavernous malformations (CCMs) are thin-walled, dilated vascular abnormalities that occur predominantly in the CNS and are a major cause of hemorrhagic strokes and seizures. Presently, there are no medical therapies for this progressive disease other than invasive neurosurgery. CCMs are caused by genetic mutations that result in the loss of a heterotrimeric adaptor complex required to negatively regulate MEKK3 signaling and the expression of the KLF2 and KLF4 transcription factors in brain endothelial cells. Recently, we have identified endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical upstream stimulators of MEKK3 signaling. However, the downstream effectors of this pathway relevant to disease pathogenesis have yet to be identified. In the neonatal mouse model of CCM disease, we have observed increased transcription of ADAMTS metalloproteases and ADAMTS-mediated processing of the ECM proteoglycan, versican, as early events in CCM development. This proposal will test the hypothesis that MEKK3-KLF2/4 signaling regulates the matrix environment, mediating versican processing by ADAMTS proteases, to promote CCM formation. Through the use of in vivo genetic mouse models and in vitro model systems, we will investigate the role of ADAMTS proteases (Aim 1) and their substrate, versican (Aim 2), as candidate downstream targets of this causal MEKK3 pathway. These studies are expected to yield new insights into the molecular molecules required to drive lesion genesis and findings may be used to direct the development of mechanism-based therapeutics for CCM disease.